Shaurya Joshi1, Jianqin Wei2, Nanette H Bishopric3. 1. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States. 2. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States. 3. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States. Electronic address: n.bishopric@miami.edu.
Abstract
RATIONALE: The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. OBJECTIVE: To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. METHODS AND RESULTS: MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. CONCLUSION: A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury.
RATIONALE: The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. OBJECTIVE: To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. METHODS AND RESULTS:MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. CONCLUSION: A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury.
Authors: Mee Young Ahn; Hae Young Chung; Wahn Soo Choi; Byung Mu Lee; Sungpil Yoon; Hyung Sik Kim Journal: Int J Oncol Date: 2010-01 Impact factor: 5.650
Authors: Edward T Chouchani; Carmen Methner; Sergiy M Nadtochiy; Angela Logan; Victoria R Pell; Shujing Ding; Andrew M James; Helena M Cochemé; Johannes Reinhold; Kathryn S Lilley; Linda Partridge; Ian M Fearnley; Alan J Robinson; Richard C Hartley; Robin A J Smith; Thomas Krieg; Paul S Brookes; Michael P Murphy Journal: Nat Med Date: 2013-05-26 Impact factor: 53.440
Authors: Jin Hou; Lei Zhao; Jing Yan; Xiaoyong Ren; Kang Zhu; Tianxi Gao; Xiaoying Du; Huanan Luo; Zhihui Li; Min Xu Journal: J Int Med Res Date: 2019-07-12 Impact factor: 1.671
Authors: Guochao Sun; Ying Lu; Yingxia Li; Jun Mao; Jun Zhang; Yanling Jin; Yan Li; Yan Sun; Lei Liu; Lianhong Li Journal: Biosci Rep Date: 2017-12-05 Impact factor: 3.840